The invention pertains to novel polycyclic ethyl alkylamides having drug and bio-affecting properties and to their preparation, pharmaceutical formulations and use. In particular, the invention concerns fluorenes bearing substituted ethyl alkylamido or ethyl cycloalkyl amido groups. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders.
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone which is synthesized and secreted primarily by the pineal gland. Melatonin levels show a cyclical, circadian pattern with highest levels occurring during the dark period of a circadian light-dark cycle. Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms and the modulation of retinal physiology.
Melatonin's structure is: ##STR2##
Recent evidence demonstrates that melatonin exerts its biological effects through specific receptors. Use of the biologically active, radiolabelled agonist .sup.125 I!-2-iodomelatonin has led to the identification of high affinity melatonin receptors in the CNS of a variety of species. The sequences of two cloned human melatonin receptors have been reported Reppert, et al., Proc. Natl. Acad. Sci. 92: 8734-8738, (1995) and Reppert, et al., Neuron 13: 1177-1185, (1994)!. In mammalian brain, autoradiographic studies have localized the distribution of melatonin receptors to a few specific structures. Although there are significant differences in melatonin receptor distribution even between closely related species, in general the highest binding site density occurs in discreet nuclei of the hypothalamus. In humans, specific .sup.125 I!-2-iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting the melatonin receptors are located within the human biological clock.
Exogenous melatonin administration has been found to synchronize circadian rhythms in rats (Cassone, et al., J. Biol. Rhythms, 1:219-229, 1986). In humans, administration of melatonin has been used to treat jet-lag related sleep disturbances, considered to be caused by desynchronization of circadian rhythms (Arendt, et al., Br. Med. J. 292:1170, 1986). Further, the use of a single dose of melatonin to induce sleep in humans has been claimed by Wurtman in International Patent Application WO 94/07487.
Thus, melatonin agonists should be particularly useful for the treatment of sleep disorders and other chronobiological disorders. Melatonin agonists would also be useful for the further study of melatonin receptor interactions as well as in the treatment of conditions affected by melatonin activity, such as depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer, premenstrual syndrome, immune disorders, inflammatory articular diseases and neuroendocrine disorders.
The compounds of this invention are melatonin agonists. However, they do not have the side effects associated with some melatonin agonists.
Aside from simple indole derivatives of melatonin itself, various bicyclic structures have been prepared and their use as melatonin ligands disclosed. In general these bicyclic amide structures can be represented as: ##STR3## wherein Z is an aryl or heteroaryl system attached by a two carbon bridge to the amide group. Some specific examples follow.
Yous, et al. in European Patent Application EPA 527 687A disclose as melatonin ligands arylethylamines 1, ##STR4## wherein Ar' is, inter alia, a substituted or unsubstituted benzob!thiophen-3-yl, benzimidazol-1-yl, benzob!furan-3-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, or indazol-3-yl radical; R.sub.1 is, inter alia, an alkyl or cycloalkyl group; and R.sub.2 is hydrogen or lower alkyl.
North et al., in WO 95/29173, published Nov. 2, 1995, discuss naphthalene derivatives of structure 2: ##STR5## wherein R.sub.1 is a group of the formula CR.sub.3 R.sub.4 (CH.sub.2).sub.p NR.sub.5 COR.sub.6 ; R.sub.2 is hydrogen, halogen, C.sub.1-6 alkyl, OR.sub.7 or CO.sub.2 R.sub.7 ; and may be the same or different substituent when q is 2; R.sub.3, R.sub.4 and R.sub.5, which may be the same or different, are hydrogen or C.sub.1-6 alkyl; R.sub.6 is C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; R.sub.7 is hydrogen or C.sub.1-6 alkyl; n is zero, 1 or 2; p is an integer of 1, 2, 3 or 4; q is 1 or 2; and the dotted lines indicate the absence or presence of an additional bond. These compounds are taught to treat chronobiological disorders.
In WO 95/17405, North et al., disclose compounds of structure 3 and teach their use in the treatment of conditions related to the melatonin system. Structure 3 is: ##STR6## wherein R.sub.1 is hydrogen, halogen or C.sub.1-6 alkyl; R.sub.2 is a group of formula --CR.sub.3 R.sub.4 (CH.sub.2).sub.p NR.sub.5 COR.sub.6 ; R.sub.3, R.sub.4 and R.sub.5, which may be the same or different, are hydrogen or C.sub.1-6 alkyl; R.sub.6 is C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; n is an integer of 2, 3 or 4; and p is an integer of 1, 2, 3 or 4.
European Patent Application EP 0 747 345 A2 discloses ethylamido-fluorenes of structure 4 and improved methods of making same. Structure 4 is: ##STR7## wherein: X=H, halogen, OH or OZ;
Z=C.sub.1-6 alkyl; --(CH.sub.2).sub.m --CF.sub.3 (m=0-2); CD.sub.3 ; or ##STR8## n=1 or 2; and R=C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-4 alkenyl, halogen substituted C.sub.1-6 alkyl, or C.sub.1-6 alkoxy substituted C.sub.1-6 alkyl. PA1 X=O, CH.sub.2, or CH (when a double bond is present); PA1 R=C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, or C.sub.1-3 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-4 alkoxyalkyl, C.sub.1-4 trifluoromethylalkyl, C.sub.1-6 aminoalkyl; and PA1 Y=H, C.sub.1-6 alkoxy or halogen. PA1 N-2-(2,10-dihydro-1H-fluoreno2,1-b!furan-10-yl)ethyl!propanamide. PA1 N-2-(8-Methoxy-10H-fluoreno1,2-d!-1,3-dioxol-10-yl)ethyl!propanamide.
The foregoing disclosures do not teach or suggest the novel melatonergic benzodioxole or dihydrobenzofurans of the present invention. The novel compounds of the present invention display melatonergic agonist activity which would not have been predicted based upon available literature.